Pharmacokinetics of ceftizoxime in animals after parenteral dosing

Abstract

The pharmacokinetic profile of ceftizoxime was studied in mice, rats, dogs, and monkeys given the drug in a single parenteral dose. The serum data after an intravenous injection were analyzed by the two-compartment open model. Cefotiam, cefmetazole, cefotaxime, and cefamandole were used as reference drugs. High concentrations of ceftizoxime were attained in the sera of all test animals and in the tissues of rats after parenteral dosing. The serum concentrations of ceftizoxime were higher than those of the other antibiotics in large animals (dogs and monkeys), but were lower in small animals (mice and rats). About 80% of ceftizoxime was excreted unchanged in the 24-h urine of all species tested. The biliary excretion of ceftizoxime was low: 3.7% in rats and 0.59% in dogs. However, therapeutically significant concentrations of ceftizoxime were found in the bile of dogs. Ceftizoxime was stable in biological fluids such as serum, urine, and tissue homogenates, but cefotaxime was unstable in rat tissue homogenates. Binding of ceftizoxime to serum protein in all species was the lowest of all the antibiotics: 31% for humans, 17% for dogs, and 32% for rats.Ceftizoxime, a new parenteral cephalosporin derivative, is more active against various gramnegative bacilli, including the opportunistic pathogens such as Enterobacter, Citrobacter spp., and Serratia marcescens, than such cephalosporins as cefotiam, cefuroxime, cefotaxime, and cefmetazole (5). In the present study the pharmacokinetics, metabolism in animals, binding to serum protein, and stability of ceftizoxime were evaluated. Cefotiam, cefamandole, cefotaxime, and cefinetazole, all recently developed cephalosporins, were used as reference drugs.MATERIALS AND METHODSAntibiotics. The compounds used in this study included ceftizoxime (FK 749, Fujisawa, Japan), cefotiam (SCE 963, Takeda, Japan), cefamandole (Eli IJlly & Co., Indianapolis, Ind.), cefmetazole (CS 1170, Sankyo, Japan), and cefotaxime (HR 756, HoechstRoussel, West Germany).Animals. The animals used in this study included 6-week-old male JCL:ICR strain mice, 6-week-old male JCL:SD strain rats, 7.5-to 15.0-kg male beagle dogs, and 5.8-to 9.1-kg male rhesus monkeys. Dosing. The antibiotics for injection were dissolved in 0.9% saline. The drugs were given in a dose of 20 mg/kg to all test animals. The volumes were: 0.25 ml per animal by the intravenous (i.v.) and subcutaneous routes to mice; 5 ml/kg of body weight by the intramuscular (i.m.) and i.v. routes to rats; and 0.5 ml/kg of body weight by the i.m. and i.v. routes to dogs and monkeys.Serum sampling. Blood samples were collected: (i) from the carotid artery of mice at specified intervals after injection; (ii) by heart puncture from rats; (iii) from the antecubital veins of dogs and monkeys. The antibiotic concentrations in the serum were bioassayed using standard solutions prepared with control serum of the respective species of animals.Pharmacokinetic analysis. The serum concentration-time data were fitted to a two-compartment open model (4) using Marqu...

Comparative Study of the Effects of Ceftizoxime, Piperacillin, and Piperacillin-Tazobactam Concentrations on Antibacterial Activity and Selection of Antibiotic-Resistant Mutants of Enterobacter cloacae and Bacteroides fragilis In Vitro and In Vivo in Mixed-Infection Abscesses

“…Similarly, all of the PIP and PT ratios of B. fragilis in both abscess combinations were comparable although they were 4-or 30-fold higher than those of CZX. This may have been due to the higher protein binding of PIP in vivo compared to that of CZX (6,12,26) and was more apparent with the anaerobe owing to the lower MIC (high inoculum) compared to that for the Enterobacter strains. The CZX ratios of B. fragilis in the two mixed infections differed 10-fold.…”

“…The antibiotic dosing regimens used in this study were chosen to produce a maximum effect in this model and took into consideration the short half-life, approximately 0.2 h, of both CZX and PIP in mice (3,26). Groups of two mice were treated subcutaneously with total CZX doses of 6 to 1,536 mg/kg/day or PIP or PT doses of 24 to 6,144 mg/kg/day.…”

Pharmacokinetics of the cephalosporin SM-1652 in mice, rats, rabbits, dogs, and rhesus monkeys

“…The tl/2(0) values of YM09330, presented by Komiya and colleagues (5), were 13.0 min in mice, 15.9 min in rats, 30.5 min in rabbits, 55.5 min in dogs, and 75.6 min in rhesus monkeys. Murakawa and associates (10) reported that the plasma half-lives of ceftizoxime, cefotiam, cefamandole, cefotaxime, and cefmetazole, administered intramuscularly to rhesus monkeys, were 47, 41, 34, 49, and 33 min, respectively. Thus, cefonicid showed the longest plasma half-life in mice, and ceforanide was the longest lasting cephalosporin in rats and rabbits.…”

“…In the tests with rabbits and dogs, blood samples were taken from each animal at 5, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min after administration. Blood specimens from each monkey were obtained at 5,10,20,30, and 45 min and 1, 2, 3, 4, 5, and 6 h after administration. Plasma was separated from these heparinized blood samples by centrifuging at 1,400 x g at 4°C, removed by aspiration, and stored at -20°C until assayed, usually within 3 days.…”

Susceptibility of intra- and extracellular Mycobacterium avium-intracellulare to cephem antibiotics

“…1). MICs of CPZ, CTX, and CZX for 90% of the isolates were 25, 6.25, and 6.25 pug/ml, respectively. It was reported that five strains of M. avium-intracellulare isolated from acquired immune deficiency syndrome patients were all resistant to 10 ,ug of CPZ per ml (3), coinciding with our result.…”